PURPOSE: Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC, CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies.
METHODS: A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC, CBD oromucosal spray compared with a control condition.
RESULTS: Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD.
CONCLUSIONS: Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC, CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.
BACKGROUND: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required.
OBJECTIVES: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.
SEARCH METHODS: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews.
SELECTION CRITERIA: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS.
DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence.
MAIN RESULTS: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.
BACKGROUND: Cannabis-based medicines are widely used in the treatment of a number of medical conditions. Unfortunately, cognitive disturbances are often reported as adverse events, although conversely, cognitive improvements have been reported. Hence, the objective of the present study was to identify, critically appraise and synthesise research findings on the potential impact of cannabis-based medicines on cognitive functioning.
METHODS: Four databases (EMBASE, PsycINFO, PubMed and Scopus) were systematically searched. Studies were included if they provided findings on the impact of cannabis-based medicines in controlled settings on cognitive functioning measured by recognised cognitive tests in human adults. Study participants were required to be their own case-control, and neither studies on abuse, abstinences, patients with severe neurodegenerative diseases nor cancer-related pain conditions were included. Screening, risk of bias assessment and data extraction were conducted independently by two researchers. Findings were tabulated and synthesised by outcome.
FINDINGS: Twenty-three studies were included, comprising a total of N = 917. Eight studies used Sativex as the cannabis-based medicine two used Epidiolex, two other studies used sprays, three studies used gelatine capsules, five smoked cannabis, two other and finally one studied cannabis withdrawal. Fifteen studies reported non-significant findings; six reported cognitive impairments; one study found cognitive improvement and a single study found improvement following withdrawal. Thirteen studies had cognitive or neuropsychological functioning as the primary outcome.
CONCLUSIONS: Due to a large heterogeneity and methodological limitations across studies, it is not possible to make any definite conclusions about the impact of cannabis-based medicines on cognitive functioning. However, the majority of high-quality evidence points in the direction that the negative impact of cannabis-based medicines on cognitive functioning is minor, provided that the doses of THC are low to moderate. On the other hand, long-term use of cannabis based medicines may still adversely affect cognitive functioning. In the studies that found impaired cognitive functioning to be significant, all of the test scores were either within the normal range or below what would be characterised as a neuropsychologically cognitive impairment.
IMPORTANCE: Cannabinoids have antispastic and analgesic effects; however, their role in the treatment of multiple sclerosis (MS) symptoms is not well defined.
OBJECTIVE: To conduct a systematic review and meta-analysis to assess the efficacy and tolerability of medicinal cannabinoids compared with placebo in the symptomatic treatment of patients with MS.
DATA SOURCES: MEDLINE and the Cochrane Library Plus up to July 26, 2016. No restrictions were applied. The search was completed with information from ClinicalTrials.gov.
STUDY SELECTION: Randomized, double-blind, and placebo-controlled trials evaluating the effect of medicinal cannabinoids by oral or oromucosal route of administration on the symptoms of spasticity, pain, or bladder dysfunction in adult patients with MS.
DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Effect sizes were calculated as standardized mean difference (SMD) for efficacy, and rate ratio (RR) for tolerability. Within each study, those SMDs evaluating the same outcome were combined before the meta-analysis to obtain a single value per outcome and study. Pooling of the studies was performed on an intention-to-treat basis by means of random-effect meta-analysis.
MAIN OUTCOMES AND MEASURES: Spasticity (on the Ashworth and Modified Ashworth scales and subjective), pain, bladder dysfunction, adverse events, and withdrawals due to adverse events.
RESULTS: Seventeen selected trials including 3161 patients were analyzed. Significant findings for the efficacy of cannabinoids vs placebo were SMD = -0.25 SD (95% CI, -0.38 to -0.13 SD) for spasticity (subjective patient assessment data), -0.17 SD (95% CI, -0.31 to -0.03 SD) for pain, and -0.11 SD (95% CI, -0.22 to -0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were RR = 1.72 patient-years (95% CI, 1.46-2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14-4.07 patient-years) in withdrawals due to adverse events. Results described a higher risk for cannabinoids. The serious adverse events meta-analysis showed no statistical significance.
CONCLUSIONS AND RELEVANCE: The results suggest a limited efficacy of cannabinoids for the treatment of spasticity, pain, and bladder dysfunction in patients with MS. Therapy using these drugs can be considered as safe.
TRIAL REGISTRATION: PROSPERO Identifier: CRD42014015391.
El propósito de este informe es presentar una revisión de los usos médicos, la eficacia y los efectos adversos de los tres medicamentos aprobados con cannabis y la ingesta de marihuana. Se realizó una revisión de la literatura utilizando términos clave de búsqueda: dronabinol, nabilona, nabiximoles, cannabis, marihuana, humo, eficacia, toxicidad, cáncer, esclerosis múltiple, náuseas, vómitos, apetito, dolor, glaucoma y efectos secundarios. Los resúmenes de la literatura incluida fueron revisados, analizados y organizados para identificar la fuerza de la evidencia en el uso médico, la eficacia y los efectos adversos de los medicamentos aprobados a base de cannabis y la marihuana medicinal. Se incluyeron un total de 68 resúmenes para su revisión. Los usos médicos más comunes de Dronabinol (Marinol) incluyen aumento de peso, náuseas y vómitos inducidos por quimioterapia (CINV) y dolor neuropático. Los usos médicos más comunes de Nabiximol (Sativex) incluyen espasticidad en esclerosis múltiple (EM) y dolor neuropático. Nabilone (Cesamet) los usos médicos más comunes incluyen CINV y dolor neuropático. Los usos médicos más comunes de la marihuana fumada incluyen dolor neuropático y glaucoma. Los usos médicos más comunes de la marihuana ingeridos incluyen la mejora del sueño, la reducción del dolor neuropático y el control de los ataques en la EM. En general, todos estos agentes comparten usos médicos similares. Los efectos adversos reportados de los tres medicamentos basados en cannabis y la marihuana muestran una importante tendencia en los efectos adversos relacionados con el sistema nervioso central (SNC), junto con los efectos adversos cardiovasculares y respiratorios. La marihuana comparte usos médicos similares con los medicamentos aprobados con cannabis, el dronabinol (Marinol), los nabiximoles (Sativex) y la nabilona (Cesamet), pero la eficacia de la marihuana para estos usos médicos no se ha determinado completamente debido a la literatura limitada y conflictiva. La marihuana medicinal también tiene efectos adversos similares a los medicamentos basados en cannabis aprobados por la FDA que consisten principalmente en efectos adversos relacionados con el SNC, pero también incluyen efectos adversos cardiovasculares y respiratorios. Finalmente, se encontró evidencia insuficiente de alto orden para apoyar el uso generalizado de la marihuana medicinal, pero una cantidad limitada de evidencia de nivel moderado apoya su uso en el manejo del dolor y las convulsiones.
Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC, CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies.
METHODS:
A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC, CBD oromucosal spray compared with a control condition.
RESULTS:
Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD.
CONCLUSIONS:
Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC, CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.
